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WO2021027722A1 - Immunomodulateur - Google Patents

Immunomodulateur Download PDF

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Publication number
WO2021027722A1
WO2021027722A1 PCT/CN2020/107788 CN2020107788W WO2021027722A1 WO 2021027722 A1 WO2021027722 A1 WO 2021027722A1 CN 2020107788 W CN2020107788 W CN 2020107788W WO 2021027722 A1 WO2021027722 A1 WO 2021027722A1
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Prior art keywords
alkylene
alkyl
membered
ring
halogen
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Chinese (zh)
Inventor
李进
张登友
白晓光
尚巳耘
洪新福
钟猛
刘利
周贤思
杨丹梅
黄昊岚
林燕萍
陈欣
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Hitgen Inc
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Hitgen Inc
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the invention relates to an immunomodulator and its use in preparing medicines.
  • IL-17 Interleukin-17
  • CTLA-8 IL-17A
  • IL-17B IL-17C
  • IL-17D IL-17D
  • IL-17E IL-25
  • IL-17F IL-17A
  • IL-17A is expressed by TH17 cells and is involved in the pathogenesis of inflammation and autoimmune diseases.
  • Human IL-17A is a glycoprotein with a molecular weight of approximately 17,000 Daltons.
  • IL-17A transmits signals to the cell via the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al.
  • IL-17A plays an important role in severe asthma and chronic obstructive pulmonary disease (COPD). Those patients usually do not respond or respond poorly to currently available drugs (Al-Ramli et al. J Allergy Clin Immunol, 2009, 123:1185-1187).
  • IL-17A levels involves many diseases, including rheumatoid arthritis (RA), bone erosion, intraperitoneal abscess, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma, and multiple Sclerosis (Gaffen, SL et al. Arthritis Research & Therapy, 2004, 6: 240-247).
  • RA rheumatoid arthritis
  • bone erosion rheumatoid arthritis
  • intraperitoneal abscess inflammatory bowel disease
  • allograft rejection psoriasis
  • atherosclerosis asthma
  • multiple Sclerosis multiple Sclerosis
  • IL-17A IL-17A-mediated autoimmune inflammatory diseases.
  • Treating animals with IL-17A neutralizing antibodies reduces the incidence and severity of the disease in autoimmune encephalomyelitis ( Komiyama Y et al. J. Immunol., 2006, 177: 566-573).
  • the clinical trials of IL-17A antibody have shown good results on IL-7A-mediated inflammatory diseases (including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis).
  • the IL-17A antibody (Cosentyx/secukinumab from Novartis) was approved by the FDA for the treatment of psoriasis in January 2015.
  • IL-17A antibodies Although there are a variety of IL-17A antibodies, few studies have been conducted on small-molecule specific inhibitors of IL-17 with oral bioavailability. In view of the cost considerations of producing antibodies and the limitation of the route of administration, the development of IL-17A small molecule inhibitor drugs has a good research and development prospect.
  • the present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkane Group), -C 0 ⁇ 4 alkylene-(5-10 membered aromatic ring), -C 0 ⁇ 4 alkylene-(5-10 membered aromatic heterocyclic ring), -NR 11 R 12 , -OR 11 ; Wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3 ⁇ 10-membered heterocycloalkyl), -C 0-4 alkylene-(5-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic ring); wherein cycloalkyl, The heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;
  • Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl), -NH 2 , -NH (C 1-10 alkyl), -N (C 1-10 alkyl) (C 1-10 alkyl);
  • R 2 is selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl);
  • R 3 and R 4 are each independently selected from hydrogen, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl),- C 0 ⁇ 4 alkylene group-(3 ⁇ 10 membered heterocycloalkyl group), -O(C 1 ⁇ 10 alkyl group), -O(C 0 ⁇ 4 alkylene group) (3 ⁇ 10 membered cycloalkyl group) , -O(C 0-4 alkylene) (3-10 membered heterocycloalkyl); wherein alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R 31 ;
  • R 3 and R 4 are connected to form a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three R 31 ;
  • Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; among them, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic
  • the heterocycle may be further substituted by one, two or three R A1 ;
  • Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene -OR A2 ,- C 0 ⁇ 4 alkylene-OC(O)R A2 , -C 0 ⁇ 4 alkylene-C(O)R A2 , -C 0 ⁇ 4 alkylene-C(O)OR A2 , -C 0 ⁇ 4 alkylene-C(O)NR A2 R A3 , -C 0 ⁇ 4 alkylene-NR A2 R A3 , -C 0 ⁇ 4 alkylene-NR A2 C(O)R A3 , -C 0 ⁇ 4 alkylene-(3 ⁇ 10 membered cycloalkyl), -C 0 ⁇ 4 alkylene-(3 ⁇ 10 member heterocycloalkyl), -C 0 ⁇ 4 alkylene-(5 ⁇
  • R A2 and R A3 are each independently selected from hydrogen and -C 1-10 alkyl
  • X 1 is selected from CR x1 or N;
  • R x1 , R x3 , and R x4 are each independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O(C 1-10 alkyl);
  • R x2 is selected from hydrogen, -C 1-10 alkyl, -C(O) (C 1-10 alkyl);
  • Ring B is selected from 3-10 membered heterocycloalkyl; wherein heterocycloalkyl may be further substituted by one, two or three R B1 ;
  • Each R B1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl), -NH 2 , -NH (C 1-10 alkyl), -N (C 1-10 alkyl) (C 1-10 alkyl);
  • L 2 is selected from -C 0 ⁇ 4 alkylene-C(O)NR L21 -, -C 0 ⁇ 4 alkylene-NR L21 C(O)-, -C 0 ⁇ 4 alkylene-S(O )NR L21 -, -C 0 ⁇ 4 alkylene-S(O) 2 NR L21 -, -C 0 ⁇ 4 alkylene-NR L21 S(O)-, -C 0 ⁇ 4 alkylene-NR L21 S(O) 2 -, -C 0 ⁇ 4 alkylene-P(O)(OH)NR L21 -, -C 0 ⁇ 4 alkylene-NR L21 P(O)(OH)-, -C 0 ⁇ 4 alkylene-C(O)-, -C 0 ⁇ 4 alkylene-NR L21 -;
  • R L21 is selected from hydrogen, -C 1-10 alkyl
  • R b and R c are each independently selected from hydrogen, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl),- C 0 ⁇ 4 alkylene-(3 ⁇ 10 membered heterocycloalkyl), -C 0 ⁇ 4 alkylene-(5 ⁇ 10 member aromatic ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 10 -Membered aromatic heterocycle), -C 0 ⁇ 4 alkylene-(5-12 membered spiro ring), -C 0 ⁇ 4 alkylene-(5-12 membered spiro heterocyclic ring), -C 0 ⁇ 4 Alkyl-(5-12 membered bridged ring), -C 0-4 alkylene-(5-12 membered bridged heterocyclic ring); among them alkyl, cycloalkyl, heterocycloalkyl, aromatic ring,
  • R a and R b are connected to form a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered aromatic heterocycle, a 5- to 12-membered spiro heterocycle, and a 5- to 12-membered bridged heterocycle; among them, heterocycloalkyl and aromatic heterocycle , Spiro heterocycles and bridged heterocycles can be further substituted by one, two or three Rd ;
  • Each R d is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene -OR d1 , -C 0 ⁇ 4 alkylene-OC(O)R d1 , -C 0 ⁇ 4 alkylene-C(O)R d1 , -C 0 ⁇ 4 alkylene-C(O)OR d1 , -C 0 ⁇ 4 alkylene-C(O)NR d1 R d2 , -C 0 ⁇ 4 alkylene-NR d1 R d2 , -C 0 ⁇ 4 alkylene-NR d1 C(O)R d2 ;
  • R d1 and R d2 are each independently selected from hydrogen, -C 1-10 alkyl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl.
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3 ⁇ 6-membered heterocycloalkyl), -C 0-2 alkylene-(5-6 membered aromatic ring), -C 0-2 alkylene-(5-6 membered aromatic heterocyclic ring); wherein cycloalkyl, The heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;
  • Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl);
  • R 2 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl);
  • R 3 and R 4 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -O(C 1 ⁇ 6 alkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl) , -O(C 0-2 alkylene) (3-6 membered heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R 31 ;
  • R 3 and R 4 are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three R 31 ;
  • Each R 31 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered heterocycloalkyl);
  • Ring A is selected from a 5- to 6-membered aromatic ring and a 5- to 6-membered aromatic heterocyclic ring; wherein the aromatic ring and the aromatic heterocyclic ring may be further substituted by one, two or three R A1 ;
  • Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 ,- C 0 ⁇ 2 alkylene-OC(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)OR A2 , -C 0 ⁇ 2 alkylene-C(O)NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 C(O)R A3 , -C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered cycloalkyl), -C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(
  • Each R A4 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 ,- C 0 ⁇ 2 alkylene-OC(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)OR A2 , -C 0 ⁇ 2 alkylene-C(O)NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 C(O)R A3 ;
  • R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl
  • X 1 is selected from CR x1 or N;
  • R x1 , R x3 , and R x4 are independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O(C 1-6 alkyl);
  • Ring B is selected from 3-6 membered heterocycloalkyl groups; wherein heterocycloalkyl groups may be further substituted with one, two or three R B1 ;
  • Each R B1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl);
  • L 2 is selected from -C 0 ⁇ 2 alkylene-C(O)NR L21 -, -C 0 ⁇ 2 alkylene-NR L21 C(O)-, -C 0 ⁇ 2 alkylene-C(O )-, -C 0 ⁇ 2 alkylene-NR L21 -;
  • R L21 is selected from hydrogen, -C 1-6 alkyl
  • R is selected from -C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered cycloalkyl), -C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene -(5 ⁇ 6 membered aromatic ring), -C 0 ⁇ 2 alkylene-(5 ⁇ 6 membered aromatic heterocyclic ring), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro ring), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro heterocycle), -C 0 ⁇ 2 alkylene-(5 ⁇ 10 member bridged ring), -C 0 ⁇ 2 alkylene-(5 ⁇ 10 member bridge hetero ring), wherein C ring is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; wherein
  • R a, R a ' are each independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen-substituted -C 1 ⁇ 6 alkyl, -C 0 ⁇ 2 alkylene group - (3-6 membered cycloalkyl), -C 0 ⁇ 2 alkylene-(3-6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(6-11 membered spiro ring), -C 0 ⁇ 2 alkylene-(6 ⁇ 11-membered spiro heterocyclic ring), -C 0-2 alkylene-(5-10 membered bridged ring), -C 0-2 alkylene-(5-10 membered bridged heterocyclic ring), -O(C 1 ⁇ 6 alkyl), -O (C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl), -O (C 0 ⁇ 2 alkylene) (3 ⁇ 6 membere
  • R a and R a' are connected to form a 3-6 membered cycloalkyl group and a 3-6 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three Ra1 ;
  • Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);
  • R b and R c are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(5 ⁇ 6 member aromatic ring), -C 0 ⁇ 2 alkylene-(5 ⁇ 6 Membered aromatic heterocycle), -C 0 ⁇ 2 alkylene-(6-11 membered spiro ring), -C 0 ⁇ 2 alkylene-(6-11 membered spiro heterocyclic ring), -C 0 ⁇ 2 alkylene Group-(5-10 membered bridged ring), -C 0-2 alkylene-(5-10 membered bridged heterocyclic ring); among them alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycl
  • R a and R b are connected to form a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered aromatic heterocycle, a 5- to 12-membered spiro heterocycle, and a 5- to 12-membered bridged heterocycle; among them, heterocycloalkyl and aromatic heterocycle , Spiro heterocycle, bridge heterocycle may be further substituted by one, two or three R d ; each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);
  • Each R d is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR d1 , -C 0 ⁇ 2 alkylene-OC(O)R d1 , -C 0 ⁇ 2 alkylene-C(O)R d1 , -C 0 ⁇ 2 alkylene-C(O)OR d1 , -C 0 ⁇ 2 alkylene-C(O)NR d1 R d2 , -C 0 ⁇ 2 alkylene-NR d1 R d2 , -C 0 ⁇ 2 alkylene-NR d1 C(O)R d2 ;
  • R d1 and R d2 are each independently selected from hydrogen, -C 1-6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl.
  • R 1 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3-6 membered heterocycloalkane) Group), -C 0 ⁇ 2 alkylene-(5-6 membered aromatic ring), -C 0 ⁇ 2 alkylene-(5-6 membered aromatic heterocyclic ring), -NR 11 R 12 , -OR 11 ; Wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3 ⁇ 6-membered heterocycloalkyl), -C 0-2 alkylene-(5-6 membered aromatic ring), -C 0-2 alkylene-(5-6 membered aromatic heterocyclic ring); wherein cycloalkyl, The heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;
  • Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl);
  • R 2 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl);
  • R 3 and R 4 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -O(C 1 ⁇ 6 alkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl) , -O(C 0-2 alkylene) (3-6 membered heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R 31 ;
  • R 3 and R 4 are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; wherein the cycloalkyl group and the heterocycloalkyl group may be further substituted by one, two or three R 31 ;
  • Each R 31 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered heterocycloalkyl);
  • Ring A is selected from 3 to 6 membered cycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; wherein the cycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further divided by one, two or three R A1 replace;
  • Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 ,- C 0 ⁇ 2 alkylene-OC(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)OR A2 , -C 0 ⁇ 2 alkylene-C(O)NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 C(O)R A3 , -C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered cycloalkyl), -C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(
  • Each R A4 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 ,- C 0 ⁇ 2 alkylene-OC(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)OR A2 , -C 0 ⁇ 2 alkylene-C(O)NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 C(O)R A3 ;
  • R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl
  • Ring B is selected from 3-6 membered heterocycloalkyl groups
  • R a is selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen-substituted -C 1 ⁇ 6 alkyl, -C 0 ⁇ 2 alkylene group - (3-6 membered cycloalkyl), - C 0 ⁇ 2 alkylene Alkyl-(3 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro ring), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro heterocyclic ring) , -C 0 ⁇ 2 alkylene group-(5 ⁇ 10 membered bridged ring), -C 0 ⁇ 2 alkylene group-(5 ⁇ 10 membered bridged heterocyclic ring), -O(C 1 ⁇ 6 alkyl group),- O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6
  • Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);
  • R b and R c are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl)-C 0 ⁇ 2 alkylene-(5 ⁇ 6 member aromatic ring), -C 0 ⁇ 2 alkylene-(5 ⁇ 6 member Aromatic heterocycle), -C 0 ⁇ 2 alkylene-(6-11 membered spiro ring), -C 0 ⁇ 2 alkylene-(6-11 membered spiro heterocyclic ring), -C 0 ⁇ 2 alkylene -(5-10 membered bridged ring), -C 0-2 alkylene-(5-10 membered bridged heterocycle); wherein alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, spiro
  • R a and R b are connected to form a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered aromatic heterocycle, a 5- to 12-membered spiro heterocycle, and a 5- to 12-membered bridged heterocycle; among them, heterocycloalkyl and aromatic heterocycle , Spiro heterocycles and bridged heterocycles can be further substituted by one, two or three Rd ;
  • Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl).
  • R 1 is selected from -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring, -NR 11 R 12 , -OR 11 ; wherein cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocyclic ring may be further substituted by one, two or three independent R 13 ;
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
  • Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl).
  • R 1 is selected from -C 1-3 alkyl, -NR 11 R 12 or -OR 11 ;
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-2 alkyl, and 3-membered cycloalkyl;
  • R13 is selected from C 1-2 alkyl.
  • R 3 and R 4 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -O( C 1-6 alkyl), -O (3-6 membered cycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl may be further substituted with one, two or three R 31 ;
  • Each R 31 is independently selected from halogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O (3--6 membered ring alkyl);
  • R 3 are each independently selected from hydrogen, -C 1 ⁇ 3 alkyl, -O (C 1 alkyl), substituted with a R 31 -C 3 alkyl group, R 31 a substituted 3-membered cycloalkyl group;
  • R 31 is selected from -C 1 alkyl and halogen; halogen is preferably F.
  • R 3 and R 4 is hydrogen.
  • Ring A is selected from 3 to 6 membered cycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; wherein the cycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further divided by one, two or three R A1 replace;
  • Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR A2 , -OC(O)R A2 ,- C(O)R A2 , -C(O)OR A2 , -C(O)NR A2 R A3 , -NR A2 R A3 , -NR A2 C(O)R A3 , 3-6 membered cycloalkyl, 3 ⁇ 6-membered heterocycloalkyl, 5 to 6-membered aromatic ring, 5 to 6-membered aromatic heterocyclic ring; wherein cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further divided by one, two or three R A4 replaced;
  • Each R A4 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR A2 , -OC(O)R A2 ,- C(O)R A2 , -C(O)OR A2 , -C(O)NR A2 R A3 , -NR A2 R A3 , -NR A2 C(O)R A3 ;
  • R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl
  • Ring A is selected from 6-membered cycloalkyl, one or two 6-membered aromatic rings substituted by R A1 ;
  • Each R A1 is independently selected from halogen
  • the halogen is preferably Cl and F.
  • ring B is a 3-6 membered oxygen-containing heterocycloalkyl group.
  • L 1 is selected from the group consisting of methylene, ethylene, n-propylidene, and isopropylidene; ring B is oxetane, tetrahydropyran ring or tetrahydrofuran ring.
  • R a is selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-11 membered spiro ring, 6 ⁇ 11 membered spiro heterocyclic ring, 5-10 membered bridged ring, 5-10 membered bridged heterocyclic ring, -O(C 1-6 alkyl), -O(3-6 membered cycloalkyl), -O(3 ⁇ 6-membered heterocycloalkyl); wherein the alkyl, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring may be further substituted with one, two or three R a1 ;
  • Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);
  • Ra is selected from hydrogen, -C 3-4 alkyl, 4-6 membered cycloalkyl, 5-6 membered oxacycloalkyl, 4-6 membered cycloalkyl substituted with one or two R a1 ;
  • Each R a1 is independently selected from -C 1 alkyl, halogen
  • the spiro ring is The bridge ring is
  • R b and R c are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro heterocycle); of which alkyl, cycloalkyl, heterocycloalkyl , Spiro heterocycle can be further substituted by one, two or three R b1 ;
  • Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);
  • R b and R c are each independently selected from hydrogen, -C 1-2 alkyl, one or two R b1 substituted -C 2 alkyl, -C 0-1 alkylene-(3 to 4-membered cycloalkyl ), a R b1 substituted -C 0 ⁇ 1 alkylene-(3-membered cycloalkyl);
  • the halogen is preferably F.
  • At least one of R b and R c is hydrogen.
  • R a and R b are connected to form a 5- to 12-membered spiro heterocyclic ring, and further, the spiro heterocyclic ring is
  • R 1 is selected from -C 1-3 alkyl, -NR 11 R 12 or -OR 11 ;
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-2 alkyl, and 3-membered cycloalkyl;
  • R 3 are each independently selected from hydrogen, -C 1 ⁇ 3 alkyl, -O (C 1 alkyl), substituted with a R 31 -C 3 alkyl group, R 31 a substituted 3-membered cycloalkyl group;
  • R 31 is selected from -C 1 alkyl, halogen
  • R a is selected from a 4-membered cycloalkyl group or a 4-membered cycloalkyl group substituted by a methyl group;
  • R d is selected from hydrogen, -C 1 alkylene-hydroxy or -C 1 alkylene-amino.
  • the compound represented by formula I is specifically:
  • the present invention also provides the use of the aforementioned compounds, or stereoisomers, or pharmaceutically acceptable salts thereof in the preparation of drugs for treating IL-17A-mediated diseases.
  • the IL-17A-mediated disease is one or more of diseases related to inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome.
  • the present invention also provides a pharmaceutical composition, which is a preparation prepared from the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, plus pharmaceutically acceptable excipients.
  • the present invention also provides the aforementioned compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrugs, or their metabolites in the preparation of therapeutic IL-17A-mediated Use in medicine for diseases.
  • the IL-17A-mediated diseases defined in the present invention are diseases in which IL-17A plays an important role in the pathogenesis of the disease.
  • the main function of IL-17A is to coordinate local tissue inflammation, thereby playing a role in various diseases.
  • IL-17A-mediated diseases include one or more of inflammation, autoimmune diseases, infectious diseases, cancer, and diseases related to precancerous syndrome. .
  • Cancer or “malignant tumor” refers to any of a variety of diseases characterized by uncontrolled abnormal cell proliferation, and the ability of affected cells to spread to other locations locally or through the bloodstream and lymphatic system The body (i.e. metastasis) and any of many characteristic structural and/or molecular characteristics.
  • Cancer cells refer to cells that undergo multiple stages of tumor progression in the early, middle or late stages. Cancers include sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer and prostate cancer.
  • the compound of formula I is used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma.
  • the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer.
  • the cancer being treated is a metastatic cancer.
  • the compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.
  • substitution refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.
  • the minimum and maximum content of carbon atoms in a hydrocarbon group are indicated by prefixes.
  • the prefix Ca to b alkyl indicates any alkyl group containing "a" to "b” carbon atoms.
  • C 1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms.
  • Alkyl refers to a saturated hydrocarbon chain having the specified number of member atoms.
  • a C 1 to C 6 alkyl group refers to an alkyl group having 1 to 6 member atoms, for example, 1 to 4 member atoms.
  • Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein.
  • Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) Base) and hexyl.
  • the alkyl group may also be part of another group, such as a C 1 to C 6 alkoxy group.
  • cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • cycloalkyl groups including multiple bicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, bicyclooctyl and the like. The following examples and names two such bicyclic alkyl polycyclic structures: Dicyclohexyl and Bicyclohexyl.
  • the straight or branched chain hydrocarbon group for example, (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.
  • Alkynyl refers to a straight chain monovalent hydrocarbon group or a branched chain monovalent hydrocarbon group containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups that have one triple bond and one double bond.
  • (C2-C6)alkynyl is meant to include ethynyl, propynyl, and the like.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Halogenalkyl means that the hydrogen atom in the alkyl group can be replaced by one or more halogen atoms.
  • a C 1-4 halogen alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms.
  • Heterocycle and “heterocycloalkyl” refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;
  • Aromatic heterocyclic ring refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, and a sulfur atom;
  • R a and R b are connected to form a heterocycloalkyl, aromatic heterocycle, spiro heterocycle or bridged heterocycle
  • R a and R b each have at least one atom through a chemical bond, so that the structural formula R "-CCN -", “- CCO- " or "-CCNS-” as part of the backbone chain of atoms with R a ring structure Together with R b constitute a heterocycloalkyl, aromatic heterocycle, spiro heterocycle or bridge heterocycle.
  • Stepoisomers include enantiomers and diastereomers;
  • pharmaceutically acceptable refers to a certain carrier, carrier, diluent, excipient, and/or the salt formed is usually chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form, and physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salts” refer to the above-mentioned compounds or their stereoisomers, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal Salt), also including quaternary ammonium salts, such as alkyl ammonium salts. These salts can be directly obtained in the final isolation and purification of the compound. It can also be obtained by mixing the above-mentioned compound or its stereoisomer with a certain amount of acid or base appropriately (for example, equivalent).
  • salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium.
  • the salt in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • one or more compounds of the present invention may be used in combination with each other.
  • the compound of the present invention can be used in combination with any other active agent to prepare drugs or pharmaceutical compositions for regulating cell function or treating diseases. If a group of compounds are used, these compounds can be administered to the subject simultaneously, separately or sequentially.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR is measured by (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetometer, and the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD),
  • the internal standard is tetramethylsilane (TMS).
  • the LC-MS measurement uses Shimadzu LC-MS 2020 (ESI).
  • Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A) was used for HPLC measurement.
  • MPLC Medium Pressure Preparative Chromatography
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • Supercritical fluid chromatography SFC
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • the retention time of (2S,3S) configuration is 2.59min
  • the retention time of (2R,3R) configuration is 3.06min( 150*3mm, 5um, isocratic 5% ethanol 1mL/min).
  • the specific rotation of (2S, 3S) configuration is 78.18° (25°C, 0.089g/100ml in methanol, wavelength 589nm)
  • the specific rotation of (2R, 3R) configuration is -72.60° (25°C, 0.098) g/100ml in methanol, wavelength 589nm).
  • the diastereoisomer mixture intermediate 2-4 (a mixture of four chiral isomers) of Example 2 was separated and purified by silica gel column chromatography (petroleum ether/methyl tert-butyl ether 100:1) to obtain the intermediate Enantiomers of form 2-4 (a mixture of enantiomers of 2-4a and 2-4b, a mixture of (2S, 3S) and (2R, 3R) configurations), take the enantiomer (1.7 g, 4.62mmol), dissolved in 20ml of dry DCM under the protection of nitrogen, cool the internal temperature to -40°C, add ZnEt2 (1M tetrahydrofuran solution, 27.73mL), stir at -30°C for 1 hour and add diiodine dropwise Methane (9.90g, 36.97mmol), keep the internal temperature not higher than -20°C during dripping.
  • the crude product was separated and purified by silica gel column (petroleum ether/methyl tert-butyl ether 100:3) to obtain 0.5 g of the mixture of Boc-protected cyclopropyl methyl ethyl 3-1 crude product and the unreacted intermediate 2-4 in the previous step ,
  • the crude product was dissolved in a mixture of tetrahydrofuran (5mL) and acetonitrile (5mL) and 5mL water, and potassium osmate dihydrate (44.3mg, 0.12mmol) and N-methyl-N-oxide morpholine (111mg, 0.96mmol), remove unreacted 2-4 by double bond double hydroxylation, stir overnight at room temperature, LC-MS monitoring shows that there is no unreacted intermediate 2-4, concentrate under reduced pressure to remove most of the organic solvent, ethyl acetate 15ml extraction, organic phase concentration, the crude product was separated and purified by silica gel column chromatography (petroleum ether
  • Intermediate 3-2 (a mixture of enantiomers) can be separated and prepared by SFC chiral column to obtain single chiral isomers 3-3a (2R, 3R) and 3-3b (2S, 3S).
  • SFC supercritical fluid chromatography
  • the retention time of (2S, 3S) configuration is 5.904 min
  • the retention time of (2R, 3R) configuration is 3.306 min ( 150*3mm, 5um, isocratic 5% ethanol 1mL/min).
  • the specific rotation of (2S, 3S) configuration is 48.755° (25°C, 0.1g/100ml in methanol, wavelength 589nm), and the specific rotation of (2R, 3R) configuration is -40.695° (25°C) , 0.1g/100ml in methanol, wavelength 589nm).
  • Example 1-1 it was prepared from 2-chloro-6-fluoro-benzaldehyde and ethyl nitroacetate.
  • Example 1-1 it was prepared from 2-chloro-3-fluoro-benzaldehyde and ethyl nitroacetate.
  • Example 8 Refer to the method of Example 8, which was obtained by condensing Boc-D-cyclobutylglycine and 1-aminomethyl-1-cyclopropanol, followed by Boc removal, MS m/z: 199[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by the condensation of Boc-D-cyclobutylglycine and cyclopropylamine, followed by de-Boc, MS m/z: 169[M+1] + .
  • Example 8 obtained by the condensation of Boc-D-cyclobutylglycine and cyclopropylmethylamine, followed by de-Boc, MS m/z: 183[M+1] + .
  • Example 8 Refer to the method in Example 8, which was obtained by condensing Boc-D-cyclobutylglycine and (1-fluorocyclopropyl)methylamine, followed by de-Boc, MS m/z: 201[M+1] + .
  • Example 8 Refer to the method of Example 8, which was obtained by condensing Boc-D-cyclobutylglycine with (1-methoxycyclopropyl)methylamine, followed by de-Boc, MS m/z: 213[M+1] + .
  • Example 8 Refer to the method of Example 8, which was obtained by condensing Boc-D-cyclobutylglycine with 2,2-difluoroethylamine and then removing Boc, MS m/z: 193[M+1] + .
  • Example 8 obtained by the condensation of Boc-D-cyclobutylglycine and 2-fluoroethylamine, followed by de-Boc, MS m/z: 175[M+1] + .
  • Example 8 Refer to the method in Example 8, which was obtained by condensing Boc-D-cyclopentylglycine with ethylamine hydrochloride and then removing Boc, MS m/z: 171[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(tetrahydrofuran-2-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 173[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(tetrahydropyran-4-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 187[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-cyclohexylglycine and ethylamine hydrochloride, followed by de-Boc, MS m/z: 285[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(4,4-difluorocyclohexyl)glycine and ethylamine hydrochloride, followed by de-Boc, MS m/z: 321[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-cyclobutylglycine and cis-2-fluoro-cyclopropylamine, followed by de-Boc, MS m/z: 187[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensation of Boc-D-cyclobutylglycine and trans-2-fluoro-cyclopropylamine, followed by de-Boc, MS m/z: 187[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensation of the corresponding Boc-D-(3-fluorocyclobutyl)glycine and ethylamine hydrochloride, followed by de-Boc, MS m/z: 175[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(3-methylcyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 171[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(1-methylcyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 171[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-(S)-(1-fluorocyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 175[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(3-methyl-3-fluorocyclobutyl)glycine with ethylamine hydrochloride, and then removing Boc, MS m/z: 189[M+1] + .
  • Example 8 Refer to the method in Example 8, obtained by condensing Boc-D-(spiro[2,3]hexane-5-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 183[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 169[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(3-(methyl)bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride and then removing Boc, MS m/z: 183[M+1] + .
  • Example 8 Refer to the method of Example 8, obtained by condensing Boc-D-(3-(fluoro)bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 187 [M+1] + .
  • HBTU 134.35mg, 353.56 ⁇ mol
  • DIPEA 114.23mg, 883.89 ⁇ mol, 153.95uL
  • 1-methyl-1H-pyrazole-5-carboxylic acid (112.01mg, 888.21 ⁇ mol) in DCM (5mL )
  • Add the intermediate 35-4 160mg, 294.63 ⁇ mol
  • step 3 react at room temperature for 2h, quench with water, extract with ethyl acetate (20ml ⁇ 3), combine the organic phases, and then respectively saturate ammonium chloride Wash with saturated brine, dry with anhydrous sodium sulfate, and spin dry under reduced pressure.
  • Example 35 Refer to the method for preparing 35-b from steps 1 to 6 in Example 35, and use the intermediate 1-5b of step 5 in Example 1 (SFC chiral resolution to obtain a single chiral isomer) and the steps in Example 6
  • the single-configuration intermediate furan o-phenylenediamine 6-6a reacted with 6-6a, after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and the intermediate amide of Example 10 10 condensation and other steps to obtain 35-a, MS m/z: 660(M+1) + .
  • the intermediate 35-6 was used as a raw material to condense with the intermediate 12 of Example 12 to obtain compound 38-b, MS m/z: 700(M+1) + .
  • the intermediate in step 5 of the preparation of another configuration 35-a another configuration of 35-6) as a raw material, and the condensation of the intermediate 12 in Example 12 to obtain compound 38-a, MS m/z: 700(M+1) + .
  • the intermediate 35-6 was used as a raw material to condense with the intermediate 13 of Example 13 to obtain compound 39-b, MS m/z: 718(M+1) + .
  • the intermediate in step 5 of the preparation of another configuration 35-a another configuration of 35-6) as the raw material, and the condensation of the intermediate 13 in Example 13 to obtain compound 39-a, MS m/z: 718(M+1) + .
  • the intermediate 35-6 was used as a raw material, and the intermediate 15 of Example 15 was condensed to obtain compound 41-b, MS m/z: 710(M+1) + .
  • the compound 41-a can be obtained by condensation with the intermediate 15 of Example 15, MS m/z: 710(M+1) + .
  • the intermediate 1-5b of step 5 in Example 1 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 are condensed, ring closed, and deprotected. Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing, and finally condensing with the intermediate amide 8-2 of Example 8 to obtain compound 62, MS m/z: 688(M+1) + .
  • the intermediate 2-6 in step 5 in Example 2 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Configuration) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 8-2 of Example 8, and then chiral resolution by SFC Compound 66-a, 66-b, 66-c, 66-d was obtained, MS m/z: 692(M+1) + .
  • the intermediate 2-6 in step 5 in Example 2 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Configuration) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 16 of Example 16, and then chiral resolution by SFC to prepare the compound 67-a, 67-b, 67-c, 67-d, MS m/z: 710(M+1) + .
  • the intermediate 2-6 in step 5 in Example 2 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Configuration) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 15 of Example 15, and then chiral resolution by SFC to prepare the compound 67-a, 67-b, 67-c, 67-d, MS m/z: 728(M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 8-2 of Example 8, and then separated by SFC chiral column Purified and prepared compound 96-a, 96-b, 96-c, 96-d, MS m/z: 692(M+1) + ; 96-a: 1 H NMR (400MHz, CD 3 OD): ⁇ 7.
  • the intermediate 4-5 in step 5 in Example 4 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 8-2 of Example 8, and then separated by SFC chiral column Purification and preparation of compound 99-a, 99-b, 99-c, 99-d, MS m/z: 692(M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 15 of Example 15, and then separated and purified by SFC chiral column Compound 100-a, 100-b, 100-c, 100-d, MS m/z: 728(M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 16 of Example 16, and then separation and purification by SFC chiral column Obtain compound 101-a, 101-b, 101-c, 101-d, MS m/z: 710(M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the furan o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Single configuration) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate amide 9 of Example 9, and then separated and purified by SFC chiral column Compound 102-a, 102-b, 102-c, 102-d was obtained, MS m/z: 734(M+1) + .
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with Example 8 intermediate 8-2 to obtain compound 104-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of propionyl group, hydrolysis and condensation to obtain compound 104-a.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 105-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of isobutyryl group, hydrolysis and condensation to obtain compound 105-a.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 106-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of pyrrolidinyl carbonyl, hydrolysis and condensation to obtain compound 106-a.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 109-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis and condensation to obtain compound 109-a.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of ethylaminocarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 110-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of ethylamine carbonyl, hydrolysis and condensation to obtain compound 110-a.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 112-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduce N-methyl-N'-cyclopropylcarbonyl, hydrolyze, and condense to obtain compound 112-a.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis and condensation to obtain compound 113-a.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 114-b.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis and condensation give compound 114-a. MS m/z: 622 (M+1) + .
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of pyrrolidinyl carbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2 to obtain compound 116-b.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of pyrrolidinyl carbonyl group, hydrolysis and condensation to obtain compound 116-a. MS m/z: 663 (M+1) + .
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with Example 8 intermediate 8-2 to obtain compound 117-b.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis and condensation to obtain compound 117-a. MS m/z: 637 (M+1) + .
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution. A single configuration) reaction, through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8 to obtain compound 118-b.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis and condensation to obtain compound 118-a. MS m/z: 623 (M+1) + .
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of ethylaminocarbonyl, hydrolysis, and condensation to obtain compound 120-a.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6b of step 6 in Example 6 were prepared by SFC chiral resolution.
  • the intermediate 1-5b of step 5 in Example 1 and the intermediate o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain another single configuration) of step 6 in Example 6 were reacted. Condensation, ring closure, deprotection, introduction of N'N-diethylcarbonyl, hydrolysis, and condensation to obtain compound 121-a.
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare the compound 123-a, 123-b, 123-c, 123-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, 1-ethyl-1H-pyrazole-
  • the 5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 123-e, 123-f, 123-g, 123-h.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of propionyl groups, hydrolysis, condensation, and then SFC Chiral resolution prepared compound 124-e, 124-f, 124-g, 124-h. MS m/z: 640(M+1) + .
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) after condensation, ring closure, deprotection, introduction of isopropionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 125-a, 125-b, 125- c, 125-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and condensation , And then chiral resolution by SFC to prepare compound 126-e, 126-f, 126-g, 126-h. MS m/z: 681 (M+1) + .
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 128-a, 128-b, 128- c,128-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, condensation, and then SFC chiral resolution to prepare compound 128-e, 128-f, 128-g, 128-h. MS m/z: 641 (M+1) + .
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, and N-methyl-N'-ethyl was introduced. The carbonyl group is hydrolyzed, condensed, and then chiralized by SFC to prepare compound 129-e, 129-f, 129-g, 129-h. MS m/z: 669 (M+1) + .
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and condensation, After chiral resolution by SFC, compound 130-e, 130-f, 130-g, 130-h was obtained. MS m/z: 655(M+1) + .
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, deprotected, introduced N,N-diethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 131-e, 131-f, 131-g, 131-h. MS m/z: 683 (M+1) + .
  • Example 132 Preparation of compound 132-a, 132-b, 132-c, 132-d, 132-e, 132-f, 132-g, 132-h
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 132 -a,132-b,132-c,132-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, N-methyl-N'-cyclopropyl was introduced
  • the compound 132-e, 132-f, 132-g, 132-h was prepared by hydrolysis, condensation, and chiral resolution by SFC. MS m/z: 681 (M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution.
  • Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare the compound 133-a, 133-b, 133-c, 133-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, 1-ethyl-1H-pyrazole-
  • the 5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 133-e,133-f,133-g,133-h.
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 134-a, 134-b, 134-c ,134-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of propionyl groups, hydrolysis, condensation, and then SFC Chiral resolution prepared compound 134-e, 134-f, 134-g, 134-h. MS m/z: 640(M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution.
  • Type) After condensation, ring closure, deprotection, introduction of isopropionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 135-a, 135-b, 135- c,135-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of isopropyl acyl group, hydrolysis, condensation, and then SFC chiral resolution to prepare compound 135-e, 135-f, 135-g, 135-h. MS m/z: 654(M+1) + .
  • Example 136 Preparation of compound 136-a, 136-b, 136-c, 136-d, 136-e, 136-f, 136-g, 136-h
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution.
  • Type) After condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2, and then chiral resolution by SFC to prepare compound 136-a, 136-b ,136-c,136-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and condensation , And then chiral resolution by SFC to prepare compound 136-e, 136-f, 136-g, 136-h. MS m/z: 681 (M+1) + .
  • Example 137 Preparation of compound 137-a, 137-b, 137-c, 137-d, 137-e, 137-f, 137-g, 137-h
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution.
  • Type) After condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 137-a,137 -b,137-c,137-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, introduced N,N-dimethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 137-e, 137-f, 137-g, 137-h. MS m/z: 655(M+1) + .
  • Example 138 Preparation of compound 138-a, 138-b, 138-c, 138-d, 138-e, 138-f, 138-g, 138-h
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 138-a,138-b,138- c,138-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, condensation, and then SFC chiral resolution to prepare compound 138-e, 138-f, 138-g, 138-h. MS m/z: 641 (M+1) + .
  • Example 139 Preparation of compound 139-a, 139-b, 139-c, 139-d, 139-e, 139-f, 139-g, 139-h
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 139- a,139-b,139-c,139-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, and N-methyl-N'-ethyl was introduced. The carbonyl group is hydrolyzed, condensed, and then chiralized by SFC to prepare compound 139-e,139-f,139-g,139-h. MS m/z: 669 (M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2, and then chiral resolution by SFC to prepare compounds 140-a, 140-b, 140-c, 140-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and condensation, After chiral resolution by SFC, compounds 140-e, 140-f, 140-g, 140-h were obtained. MS m/z: 655(M+1) + .
  • Example 141 Preparation of compound 141-a, 141-b, 141-c, 141-d, 141-e, 141-f, 141-g, 141-h
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 141-a,141 -b,141-c,141-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, deprotected, introduced N,N-diethylcarbonyl, and hydrolyzed , Condensation, and chiral resolution by SFC to prepare compound 141-e,141-f,141-g,141-h. MS m/z: 683 (M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 142 -a,142-b,142-c,142-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, N-methyl-N'-cyclopropyl was introduced
  • the compound 142-e, 142-f, 142-g, 142-h was prepared by hydrolysis, condensation, and SFC chiral resolution.
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution.
  • Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare the compound 143-a,143-b,143-c,143-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, 1-ethyl-1H-pyrazole-
  • the 5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 143-e,143-f,143-g,143-h.
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 144-a, 144-b, 144-c ,144-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of propionyl groups, hydrolysis, condensation, and then SFC Compound 144-e, 144-f, 144-g, 144-h were prepared by chiral resolution. MS m/z: 640(M+1) + .
  • Example 145 Preparation of compound 145-a, 145-b, 145-c, 145-d, 145-e, 145-f, 145-g, 145-h
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution.
  • Type) After condensation, ring closure, deprotection, introduction of isopropanoyl group, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 145-a,145-b,145- c,145-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of isopropyl acyl group, hydrolysis, condensation, and then SFC chiral resolution prepared compound 145-e, 145-f, 145-g, 145-h. MS m/z: 654(M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution.
  • Type) After condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 8 intermediate 8-2, and then chiral resolution by SFC to prepare compound 146-a, 146-b ,146-c,146-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and condensation , And then chiral resolution by SFC to prepare compound 146-a, 146-b, 146-c, 146-d. MS m/z: 681 (M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2, and then chiral resolution by SFC to prepare compound 147-a,147 -b,147-c,147-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, introduced N,N-dimethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 147-e,147-f,147-g,147-h. MS m/z: 655(M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 148-a, 148-b, 148- c,148-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was subjected to condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, condensation, and then SFC chiral resolution prepared compound 148-e, 148-f, 148-g, 148-h. MS m/z: 641 (M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 149- a, 149-b, 149-c, 149-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, and deprotected, and N-methyl-N'-ethyl was introduced. The carbonyl group is hydrolyzed, condensed, and then chiralized by SFC to prepare compound 149-e, 149-f, 149-g, 149-h. MS m/z: 669 (M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compounds 150-a, 150-b, 150-c, 150-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and condensation, After chiral resolution by SFC, compounds 150-e, 150-f, 150-g, 150-h were obtained. MS m/z: 655(M+1) + .
  • Example 151 Preparation of compound 151-a, 151-b, 151-c, 151-d, 151-e, 151-f, 151-g, 151-h
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with the intermediate 8-2 of Example 8, and then chiral resolution by SFC to prepare compound 151-1,151 -b,151-c,151-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 was condensed, closed, deprotected, introduced N,N-diethylcarbonyl, and hydrolyzed , Condensation, and then chiral resolution by SFC to prepare compound 151-1e,151-f,151-g,151-h. MS m/z: 683 (M+1) + .
  • Example 152 Preparation of compound 152-a, 152-b, 152-c, 152-d, 152-e, 152-f, 152-g, 152-h
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution.
  • Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with Example 8 Intermediate 8-2, and then SFC chiral resolution to prepare compound 152 -a,152-b,152-c,152-d.
  • step 6 o-phenylenediamine 6-6a (prepared by SFC chiral resolution to obtain a single configuration) in Example 6 through condensation, ring closure, and deprotection, N-methyl-N'-cyclopropyl was introduced
  • the carbonyl carbonyl group is hydrolyzed, condensed, and then chiralized by SFC to prepare compound 152-e, 152-f, 152-g, 152-h.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with L-cyclobutyl-N-ethylglycamine amide to obtain compound 153-b;
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 154-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 155-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 36-6 was used as a raw material to condense with D-isopropyl-N-ethylglycineamide to obtain compound 156-b.
  • compound 156- can be obtained by condensation with D-isopropyl-N-ethylglycamine amide a.
  • the intermediate 36-6 was used as a raw material to condense with D-tert-butyl-N-ethylglycineamide to obtain compound 157-b.
  • compound 157- can be obtained by condensation with D-tert-butyl-N-ethylglycamine amide a.
  • Example 158 Preparation of compound 158-a, 158-b, 158-c, 158-d, 158-e, 158-f, 158-g, 158-h
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 158-a, 158-b, 158-c, 158-d.
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6a in step 6 in Example 6 were condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 158-e, 158-f, 158-g, 158-h. MS m/z: 680 (M+1) + .
  • Example 159 Preparation of compound 159-a, 159-b, 159-c, 159-d, 159-e, 159-f, 159-g, 159-h
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 159-a, 159-b, 159-c, 159-d.
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6a in step 6 in Example 6 were condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 159-e, 159-f, 159-g, 159-h. MS m/z: 694 (M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6a in step 6 in Example 6 are condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 160-e, 160-f, 160-g, 160-h. MS m/z: 680 (M+1) + .
  • Example 161 Preparation of compound 161-a, 161-b, 161-c, 161-d, 161-e, 161-f, 161-g, 161-h
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 161-a, 161-b, 161-c, and 161-d.
  • o-phenylenediamine 6-6a in step 6 was subjected to condensation, ring closure, and deprotection. , Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycineamide, and then undergo chiral resolution by SFC to prepare compound 161-e,161 -f,161-g,161-h. MS m/z: 694 (M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 162-a, 162-b, 162-c, 162-d.
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 are condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 162-e, 162-f, 162-g, 162-h. MS m/z: 680 (M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) after condensation, ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral SFC Resolved to prepare compound 163-a, 163-b, 163-c, 163-d.
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 are condensed, ring closed, and removed. Protection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 163-e, 163-f,163-g,163-h. MS m/z: 694 (M+1) + .
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 164-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 165-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) through condensation, ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 166-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 167-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 168-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 169-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 170-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 171-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 172-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide to obtain compound 173-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7 to obtain compound 174-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed. , Deprotection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7 to obtain compound 174-a.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide to obtain compound 175-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 176-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 177-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 178-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure. Type) through condensation, ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 179-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 180-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 181-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 182-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 183-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution to obtain a single structure.
  • Type) After condensation, ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide to obtain compound 184-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) through condensation, ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide to obtain compound 185-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6b in step 6 in Example 6 were used to prepare a single structure. Type) after condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycamine amide to obtain compound 186-b.
  • the intermediate 3-3b in step 3 in Example 3 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) after condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycineamide to obtain compound 187-b.
  • the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally with D-tert-butyl-N-ethylglycamine amide to obtain compound 188-b.
  • the intermediate 1-5b in step 5 in Example 1 and the o-phenylenediamine 6-6a in step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) are condensed and the ring is closed.
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 189-a,189 -b,189-c,189-d.
  • Example 190 Preparation of compound 190-a, 190-b, 190-c, 190-d, 190-e, 190-f, 190-g, 190-h
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by chiral resolution of a single structure. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 190-a,190 -b,190-c,190-d.
  • the intermediate 2-6 in step 5 in Example 2 and the o-phenylenediamine 6-6a in step 6 in Example 6 were condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 190-e,190-f,190-g,190- h. MS m/z: 644 (M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 191-a,191 -b,191-c,191-d.
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6a in step 6 in Example 6 are condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 191-e,191-f,191-g,191- h. MS m/z: 630 (M+1) + .
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 192-a,192 -b,192-c,192-d.
  • the intermediate 4-5 in step 5 in Example 4 and the o-phenylenediamine 6-6a in step 6 in Example 6 are condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 192-e,192-f,192-g,192- h. MS m/z: 644 (M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 193-a,193 -b,193-c,193-d.
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 are condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl group, hydrolysis, and finally condensation with D-isopropyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 193-e,193-f,193-g,193- h. MS m/z: 630 (M+1) + .
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6b in step 6 in Example 6 were prepared by SFC chiral resolution. Type) through condensation, ring closure, deprotection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycineamide, and then chiral resolution by SFC to prepare compound 194-a,194 -b,194-c,194-d.
  • the intermediate 5-5 in step 5 in Example 5 and the o-phenylenediamine 6-6a in step 6 in Example 6 are condensed, ring closed, and removed. Protection, introduction of methoxycarbonyl, hydrolysis, and finally condensation with D-tert-butyl-N-ethylglycamine amide, and then chiral resolution by SFC to prepare compound 194-e,194-f,194-g,194- h. MS m/z: 644 (M+1) + .
  • the intermediate 2-6 in step 5 in Example 2 and the pyran o-phenylenediamine 7-5 in step 5 in Example 7 are condensed, ring closed, and deprotected. Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, finally condense with D-isopropyl-N-ethylglycamine amide, and then undergo chiral resolution by SFC to prepare compound 200-a,200- b,200-c,200-d. MS m/z: 694 (M+1) + .
  • the intermediate 2-6 of step 5 in Example 2 and the pyran o-phenylenediamine 7-5 in step 5 of Example 7 were condensed, ring closed, and deprotected. , Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze, and finally condense with D-tert-butyl-N-ethylglycamine amide, and then undergo chiral resolution by SFC to prepare compound 201-1,201 -b,201-c,201-d. MS m/z: 708 (M+1) + .

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Abstract

L'invention concerne un immunomodulateur, et spécifiquement un composé qui inhibe l'IL-17A et son utilisation en tant qu'immunomodulateur dans la préparation d'un médicament. L'invention concerne l'utilisation d'un composé tel que représenté dans la formule I ou un stéréoisomère de celui-ci dans la préparation d'un médicament pour l'inhibition d'IL-17A, ceci offrant une nouvelle option pour le criblage clinique et/ou la préparation d'un médicament pour le traitement de maladies associées à l'activité de l'IL -17A.
PCT/CN2020/107788 2019-08-09 2020-08-07 Immunomodulateur Ceased WO2021027722A1 (fr)

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WO2023275301A1 (fr) 2021-07-01 2023-01-05 UCB Biopharma SRL Dérivés d'imidazotriazine utiles comme modulateurs de l'il-17
WO2024017880A1 (fr) 2022-07-22 2024-01-25 UCB Biopharma SRL Dérivés d'imidazotriazine utilisés comme modulateurs de l'il-17
AU2021306755B2 (en) * 2020-07-04 2024-05-30 Hitgen Inc. Immunomodulator

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CA3181676A1 (fr) 2020-04-30 2021-11-04 Janssen Pharmaceutica Nv Imidazopyridazines en tant que modulateurs de l'il-17
WO2021250194A1 (fr) 2020-06-12 2021-12-16 Leo Pharma A/S Modulateurs à petites molécules d'il-17
US20230227435A1 (en) 2020-06-18 2023-07-20 Leo Pharma A/S Small molecule modulators of il-17
WO2021255085A1 (fr) 2020-06-18 2021-12-23 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2021255086A1 (fr) 2020-06-18 2021-12-23 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023025783A1 (fr) 2021-08-23 2023-03-02 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023111181A1 (fr) 2021-12-16 2023-06-22 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023166172A1 (fr) 2022-03-04 2023-09-07 Leo Pharma A/S Modulateurs à petites molécules d'il-17
TW202430165A (zh) 2022-12-02 2024-08-01 丹麥商理奧藥品公司 Il-17之小分子調節劑

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WO2023275301A1 (fr) 2021-07-01 2023-01-05 UCB Biopharma SRL Dérivés d'imidazotriazine utiles comme modulateurs de l'il-17
WO2024017880A1 (fr) 2022-07-22 2024-01-25 UCB Biopharma SRL Dérivés d'imidazotriazine utilisés comme modulateurs de l'il-17

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